Process for the production of 1,4,5,6-tetrahydropyrazine-2-carboxylic acid amides

ABSTRACT

A process for the production of 1,4,5,6-tetrahydropyrazine-2-carboxylic acid amides of the general formula (I), where R 1  means hydrogen, alkyl, cycloalkyl or arylalkyl, R 2  means alkyl, aryl or arylalkyl and R 3 , R 4  and R 5  mean independently from each other hydrogen, alkyl, aryl or arylalkyl or R 2  forms an alicyclic system with R 3  or R 4  and the adjacent C atom(s), R 6  being hydrogen or acyl. The products are obtained from the corresponding tetrahydropyrazine carboxylic acid nitriles and olefins or corresponding carbenium ion precursors and possibly carboxylic acids in a Ritter reaction. The products are new and can be used, for example, for the production of piperazine carboxylic acid amides. ##STR1##

The present invention relates to a process for preparing1,4,5,6-tetrahydropyrazine-2-carboxamides of the general formula##STR2## where R¹ is hydrogen, a C₁ -C₃₀ -alkyl radical, acycloaliphatic radical having 3 to 8 ring members, an aromatic radicalor an araliphatic radical having 7 to 12 carbon atoms, and

(a) R² is a C₁ -C₆ -alkyl radical, an aryl radical or an arylalkylradical and R³, R⁴ and R⁵ independently of one another are eachhydrogen, C₁ -C₆ -alkyl radicals, aryl radicals or arylalkyl radicals,or

(b) R² joins with R³ or R⁴ and the adjacent carbon atom(s) to form amono- or polycyclic alicyclic system which may optionally be substitutedby one or more C₁ -C₄ -alkyl groups, and R⁵ and R⁴ or R³ are each asdefined above,

and R⁶ is hydrogen or a group of the formula R⁷ --C(═O)-- where R⁷ ishydrogen or optionally substituted C₁ -C₆ -alkyl.

Here and below, alkyl radicals are in each case straight-chain orbranched primary, secondary or tertiary alkyl groups, i.e. for examplemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,isobutyl, pentyl, isopentyl, neopentyl, hexyl, octyl, etc.

Substituted alkyl is for example alkoxyalkyl groups or haloalkyl groups,in particular perfluoroalkyl groups such as, for example,trifluoromethyl.

Cycloaliphatic radicals are cycloalkyl groups, i.e. for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Aryl radicals or aromatic radicals are mono- or polycyclic aromaticgroups which may optionally be substituted by C₁ -C₄ -alkyl groups orhalogens, i.e. for example phenyl, 1-naphthyl, 2-naphthyl, o-tolyl,m-tolyl, p-tolyl, xylyls, chlorophenyls, etc.

Correspondingly, arylalkyl radicals or araliphatic radicals arearyl-substituted alkyl radicals, in particular benzyl, 1-phenylethyl or2-phenylethyl.

It is known that pyrazinecarboxylic acids and derivatives thereof suchas esters and amides can be hydrogenated using heterogeneous catalysts(for example Pd/C). However, this hydrogenation usually leads to thecorresponding piperazine derivative, i.e. the heteroaromatic ringbecomes fully hydrogenated. Partial hydrogenation to thetetrahydropyrazine system has only been observed in exceptional cases,in which the isolation of a pure product in the case of thetetrahydropyrazinecarboxylic esters caused problems and thecorresponding amide was not obtainable by this route. (E. Felder et al.,Helv. Chim. Acta, 1960, 43, 888-896).

It is an object of the present invention to provide an industrial routeto 1,4,5,6-tetrahydropyrazine-2-carboxamides substituted at the amidenitrogen. These previously unknown compounds are to provide alternativeaccess to the corresponding piperazinecarboxamides, of which for examplethe (S)-piperazine-tert-butylcarboxamide is a building block of anactive compound for the treatment of AIDS (U.S. Pat. Nos. 5,413,999,5,527,799, 5,668,132 and 5,717,097)

According to the invention, this object is achieved by the process of ofthe invention and the compounds of of the invention.

It has been found that the 2-cyano-1,4,5,6-tetrahydropyrazines of thegeneral formula ##STR3## where R¹ is as defined above, react in thepresence of a strong acid with compounds of the general formula ##STR4##where R², R³, R⁴ and R⁴ are each as defined above and Q is a group whichcan be removed to leave a carbenium ion, in a Ritter reaction. It isprobable that in this reaction a nitrilium salt is initially formed bythe addition of the carbenium ion, formed from IIIa by protonationand/or from IIIb by removal of the group Q, to the cyano group, thenitrilium salt then being hydrolysed to the amide. If the reaction iscarried out in the presence of a carboxylic acid of the formula

    R.sup.7 --COOH                                             IV

where R⁷ is as defined above, position 1 of the tetrahydropyrazine ringis additionally selectively acylated, affording a product (I) where R⁶═R⁷ --C(═O)--. Without the addition of a carboxylic acid, thecorresponding compound where R⁶ ═H is obtained. The embodiment with theaddition of a carboxylic acid is preferred, since the acyl group may actas a protecting group in subsequent syntheses, permitting selectivereactions at the nitrogen atom in position 4.

Particular preference is given to using carboxylic acids where R⁷ ishydrogen, a C₁ -C₃ -alkyl group or a C₁ -C₃ -perfluoroalkyl group, inparticular acetic acid (R⁷ ═CH₃) or trifluoroacetic acid (R⁷ ═CF₃).

Suitable 2-cyano-1,4,5,6-tetrahydropyrazines according to formula II arethose having hydrogen in position 3 (R¹ ═H) and those having C₁ -C₃₀-alkyl radicals, cycloaliphatic radicals having 3 to 8 ring members,aromatic radicals or araliphatic radicals having 7 to 12 carbon atoms.

These compounds are easily obtainable from α-dicarbonyl compounds,ethylenediamine and cyanide by the process described in EuropeanPublished Patent Application No. 0175364 and U.S. Pat. No. 4,734,499.Preference is given to using the compound which is unsubstituted inposition 3 (R¹ ═H).

Additionally, it has been found that corresponding compounds whichalready carry an acyl group in position 1 (at the nitrogen atom)surprisingly do not participate in the reaction of the invention at all,or only to a very small extent, although they should afford the sameproducts. On the other hand, it has been found that even under drasticconditions (excess of carboxylic acid, presence of thionyl chloride)selective N¹ -acylation occurs, and that virtually no N¹,N⁴ -diacylatedproducts are obtained.

The 2-cyano-1,4,5,6-tetrahydropyrazines (II) can be employed as freebases and as salts. Suitable salts are in particular the monosalts withstrong acids, for example the hydrohalides, the hydrogen sulfate or thesulfonates. Compared with the free bases, these salts also have theadvantage of a better storage stability. Particular preference is givento the monomethanesulfonate.

Suitable strong acids in the reaction medium are correspondingly theso-called mineral acids, such as, for example, sulfuric acid, phosphoricacid and perchloric acid, sulfonic acids such as, for example,methanesulphonic acid, benzenesulfonic acid or polymeric sulfonic acids(acidic ion exchangers), strong carboxylic acids, such as, for example,formic acid or trifluoroacetic acid, or else Lewis acids, such as, forexample, boron trifluoride. Particular preference is given tomethanesulfonic acid.

Suitable compounds of the formulae IIIa and IIIb are alkenes (IIIa) andalso compounds which can form carbenium ions on removal of a group Qunder the action of a strong acid (IIIb).

Suitable alkenes are open-chain alkenes where R² is a C₁ -C₆ -alkylradical, an aryl radical or an arylalkyl radical and R³, R⁴ and R⁵independently of one another are each hydrogen, C₁ -C₆ -alkyl, aryl orarylalkyl, and also cyclic alkenes. In the cyclic alkenes, the doublebond may be exocyclic, so that R² joins with R³ and the adjacent carbonatom to form a mono- or polycyclic alicyclic system, or it may beendocyclic, so that R² together with R⁴ and the two adjacent carbonatoms forms a mono- or polycyclic alicyclic system. Examples ofopen-chain alkenes are propene, 1-butene, 2-butene, isobutene, thevarious isomeric pentenes and hexenes, styrene, alkylbenzene andstilbenes.

Alkenes having an exocyclic double bond are, for example,methylenecyclohexane or the bicyclic camphene. Alkenes having anendocyclic double bond include, for example, the cycloalkenes, such ascyclopentene, cyclohexene and cycloheptene.

A particularly preferred alkene (IIIa) is isobutene (R² ═R³ ═CH³, R⁴ ═R⁵═H).

Of the compounds (IIIb) which afford carbenium ions on removal of agroup Q in the presence of strong acids, the alcohols (Q═OH) andderivatives thereof, such as, for example, esters (Q=acyloxy) or ethers(Q=alkoxy) are of particular importance. Isopropyl and tert-butylalcohol, methyl tert-butyl ether, tert-butyl acetate and cyclohexanolmay be mentioned as examples.

Of course, the invention also includes the joint use of alkenes (IIIa)with the corresponding compounds of the formula IIIb, i.e. for exampleisobutene together with tert-butyl alcohol.

The reaction conditions depend on the starting materials employed andcan be varied within wide limits. The acid itself, i.e. for examplesulphuric acid or the carboxylic acid (IV) which is optionally added,can serve as solvent, but it is also possible to add further polar orapolar inert solvents.

The reaction temperature is advantageously in the range of 0-50° C.,preferably 15-30° C.

It is advantageous to avoid high concentrations of alkene (IIIa) or ofthe compound IIIb in the reaction mixture, so as not to favor theformation of polymers and oligomers. To this end, the alkene or thecompound IIIb is not precharged but added slowly at the rate of thereaction.

Work-up can be carried out by conventional methods, for example byextracting the optionally neutralized reaction mixture. In manyinstances, the product formed precipitates after basic work-up and canbe separated off by filtration or centrifugation.

The following examples illustrate the practice of the process accordingto the invention.

EXAMPLES

Example 1

1-Acetyl-1,4,5,6-tetrahydropyrazine-2-tert-butylcarboxamide

(I; R¹ ═R⁴ ═R⁵ ═H, R² ═R³ ═CH₃, R⁶ =acetyl)

At room temperature, 70 g (0.77 mol) of methanesulfonic acid and then20.0 g (184 mmol) of 2-cyano-1,4,5,6-tetrahydropyrazine were addedslowly to 100 ml (1.75 mol) of acetic acid. At 25° C., 23.0 g (410 mmol)of isobutene were passed into this mixture, and the mixture was stirredfor 5 h.

With cooling, the mixture was then neutralized using 30% strengthaqueous sodium hydroxide solution, the temperature at all times beingkept below 30° C. The mixture, which had been adjusted to pH 8-10, wasextracted three times with 200 ml of methyl ethyl ketone each time. Thecombined organic phases were dried over magnesium sulphate and thesolvent was distilled off. The residue (41.2 g) was dissolved in 80 mlof hot ethyl acetate. After cooling to 20° C., 500 ml of hexane wereadded, the mixture was cooled further to 0° C. and the precipitatedproduct was filtered off after 1 h and dried.

Yield: 32.6 g (79%) of a light-beige powder m.p.: 151.3-152.6° C.

¹ H NMR ( D₆ !DMSO, 400 MHz): δ=1.27 (s, 9H) 1.89 (s, 3H); 3.06-3.12 (m,2H); 3.31-3.40 (m, 2H); 6.46 (br. s, 1H); 6.59 (br. s, 1H); 6.80 (d,J=7.2 Hz, 1H).

Example 2

1-Acetyl-1,4,5,6-tetrahydropyrazine-2-tert-butylcarboxamide

Similarly to Example 1, 22 g (0.23 mol) of methanesulfonic acid and 10 g(92 mmol) of 2-cyano-1,4,5,6-tetrahydropyrazine were added to 30 ml ofacetic acid and 20 ml of water, and 8.65 g (154 mmol) of isobutene werepassed in.

After the reaction had ended, the mixture was neutralized with 119 g of30% strength aqueous sodium hydroxide solution at 5° C. and adjusted topH 11.6. The precipitated product was filtered off, washed with 10 ml ofice-water and dried under reduced pressure.

Yield: 28.9 g of a light-yellow powder having a content of 58%(equivalent to 80% of theory).

Example 3

1-Propionyl-1,4,5,6-tetrahydropyrazine-2-tert-butylcarboxamide

(I; R¹ ═R⁴ ═R⁵ ═H, R² ═R³ ═CH₃, R⁶ =propionyl)

The compound was prepared similarly to Example 1 using propionic acidinstead of acetic acid.

Yield: 75% m.p.: 172.4-172.6° C.

¹ H NMR (CDCl₃, 400 MHz): δ=1.09 (t, J=7.3 Hz, 3H); 1.37 (s, 9H); 2.39(q, J=7.3 Hz, 2H); 3.28 (m, 2H); 3.57 (m, 2H); 5.41 (br. s, 1H); 5.49(br. s, 1H); 7.09 (d, J=6.3 Hz, 1H)

¹³ C NMR (CDCl₃, 100 MHz): δ=9.44 (CH₃); 27.55 (CH₂); 29.12 (CH₃); 38.29(CH₂); 42.19 (CH₂); 50.92 (C); 106.66 (C); 132.20 (CH); 165.21 (C═O);177.20 (C═O).

Example 4

1-Isobutyryl-1,4,5,6-tetrahydropyrazine-2-tert-butylcarboxamide

(I; R¹ ═R⁴ ═R⁵ ═H, R² ═R³ ═CH₃, R⁶ =isobutyryl)

The compound was prepared similarly to Example 1 using isobutyric acidinstead of acetic acid.

Yield: 48% m.p.: 180.0-184.4° C.

¹ H NMR (CDCl₃, 400 MHz): δ=1.07 (d, J=6.5 Hz, 6H); 1.37 (s, 9H); 2.82(sept, J=6.5 Hz, 1H); 3.27 (m, 2H); 3.6 (br. m, 2H); 4.94 (br. s, 1H);5.48 (br. s, 1H); 7.12 (d, J=6.3 Hz, 1H).

¹³ C NMR (CDCl₃, 100 MHz): δ=19.36 (CH₃); 29.07 (CH₃); 32.50 (CH); 38.39(CH₂) 42.42 (CH₂); 50.94 (C); 106.73 (C); 132.07 (CH); 165.21 (C═O);180.85 (C═O).

Example 5

1-(Methoxyacetyl)-1,4,5,6-tetrahydropyrazine-2-tert-butylcarboxamide

(I; R¹ ═R⁴ ═R⁵ ═H, R² ═R³ ═CH₃, R⁶ =methoxyacetyl)

The compound was prepared similarly to Example 1 using methoxyaceticacid instead of acetic acid.

Yield: 52% m.p.: 185.5-189.9° C.

¹ H NMR (CDCl₃, 400 MHz): δ=1.38 (s, 9H); 3.33 (m, 2H); 3.41 (s, 3H);3.59 (m, 2H); 4.17 (s, 2H); 5.12 (br. s, 1H); 5.47 (br. s, 1H); 7.11 (d,J=6.3 Hz, 1H).

¹³ C NMR (CDCl₃, 100 MHz):=29.12 (CH₃); 38.27 (CH₂); 42.11 (CH₂); 51.09(C); 59.31 (CH₃ O); 70.86 (CH₂ O); 105.48 (C); 132.72 (CH); 164.53(C═O); 172.39 (C═O);

Example 6

1-Trifluoroacetyl-1,4,5,6-tetrahydropyrazine-2-tert-butylcarboxamide

(I; R¹ ═R═R⁴ ═R⁵ ═H, R² ═R³ ═CH₃, R⁶ ═trifluoroacetyl--from themethanesulphonic acid salt of 2-cyano-1,4,5,6-tetrahydropyrazine)

Under argon, 50 ml of trifluoroacetic acid were precharged in a 500 mlflask. At 21° C., 12.5 g of methanesulfonic acid were added dropwise,and 20 g of the methanesulphonic acid salt of2-cyano-1,4,5,6-tetrahydropyrazine (97 mmol) were then added a little ata time, a slightly exothermic reaction being observed. Within 1 h, 10 g(178 mmol) of isobutene were then added at 20° C. The reaction mixturewas stirred for a further 2 h at 20° C. and then, at this temperature,admixed dropwise with 13.3 g (111 mmol) of thionyl chloride and stirredfor a further 20 h. 250 ml of dichloromethane and, a little at a time,25 g of sodium acetate were then added. After the crude solution wasfiltered through Celite®, 30 ml of water were added and the phases wereseparated. The organic phase was evaporated to dryness. The remainingcrude product (27.88 g) was chromatographed over 300 g of silica gelusing ethyl acetate/methanol (4:1).

Yield (GC): 29.2% m.p.: 158.-160° C. (from n-butyl acetate).

¹ H NMR (CDCl₃, 400 MHz) : δ1.35 (s, 9H); 3.43 (br. s, 2H); 3.74 (br. s,2H); 5.32 (br. s, 1H); 5.53 (br. s, 1H); 7.06 (d, J=6 Hz, 1H).

¹³ C NMR (CDCl₃, 100 MHz): δ=28.9; 42.3; 42.8; 51.2; 105.9; 116.3(J_(C-F) =288 Hz); 133.2; 154.5 (J_(C-F) =35 Hz); 163.7.

MS: m/z=57 (100%), 279 (M⁺, 6.2%).

Comparative Example

Attempted preparation of1-acetyl-1,4,5,6-tetrahydropyrazine-2-tert-butylcarboxamide from1-acetyl-2-cyano-1,4,5,6-tetrahydropyrazine

A) ¹ -Acetyl-2-cyano-1,4,5,6-tetrahydropyrazine

10.0 ml (106 mmol) of acetic anhydride and 8.0 ml (99 mmol) of pyridinewere added to 5.10 g (47 mmol) of 2-cyano-1,4,5,6-tetrahydropyrazine,and the mixture was stirred at 20° C. for 18 h. After aqueous work-up,the reaction product was extracted three times with 100-200 ml of ethylacetate each. The combined organic extracts were dried over magnesiumsulphate and concentrated. The crude product was then purified by flashchromatography (silica gel 40×3 cm, ethyl acetate:hexane=4:1, R_(f)=0.25). the fraction having R_(f) =0.25 (5.82 g) was taken up in 40 mlof diethyl ether and the precipitated solid was filtered off and dried.

m.p.: 100.5-102.0° C. Yield: 5.62 g (80%) of a slightly yellow solid

NMR data:

The rotation of the acetyl group around the amide bond is stronglyhindered, so that separate signals for the two possible conformers (Eand Z form) of a ratio of intensities of 3:2 are obtained in the NMRspectrum. Here, the two conformers are labelled A and B, the letter Abeing assigned arbitrarily to the conformer present in a greater amount.

¹ H NMR ( D₆ !DMSO, 400 MHz):

Conformer A: δ=2.15 (s, 3H); 3.14-3.20 (m, 2H); 7.09 (d, J=7.0 Hz, 1H);7.46 (br. s, 1H).

Conformer B: δ 2.01 (s, 3H); 3.25-3.33 (m, 2H); 6.90 (d, J=7.0 Hz, 1H);7.01 (br. s, 1H).

Conformer A+B: δ=3.44-3.56 (m, 2+2H) ¹³ C NMR ( D₆ !DMSO, 100 MHz):

Conformer A: δ=22.38 (CH₃); 80.67 (C); 119.48 (C≡N); 138.59 (CH); 168.50(C═O).

Conformer B: δ=20.97 (CH₃); 81.94 (C); 118.35 (C≡N); 137.16 (CH); 166.65(C═O).

Assignment unclear: δ=36.17 (CH₂); 41.45 (CH₂); 41.69 (CH₂); 41.74(CH₂).

B) Attempted reaction with isobutene

At 20° C., 4.91 g of 1-acetyl-2-cyano-1,4,5,6-tetrahydropyrazine (32.5mmol) were added to a solution of 12.73 g of 98% strength sulphuric acid(130 mmol) in 50 ml of glacial acetic acid. Over 3 h, 3.62 g ofisobutene (64.5 mmol) were passed through the solution at a constanttemperature, and the reaction mixture was then stirred for a further 3h. The dark brown suspension was poured onto 106 g of ice and adjustedto a pH 8 with 30% strength aqueous sodium hydroxide solution at T<20°C. A fine precipitate (Na₂ SO₄) was filtered off and the filtrate wascontinuously extracted with dichloromethane overnight. Only a littleblack solid was isolated by evaporating the organic phase. The aqueousphase was concentrated. The solid residue was suspended in 80 ml ofboiling ethanol, about 2/3 of the amount dissolving. Evaporation gave6.8 g of an orange solid. This was taken up in hot isopropanol and theinsoluble part was filtered off. 3.52 g of1-acetyl-1,4,5,6-tetrahydropyrazine-2-carboxamide crystallized from theisopropanol solution as a beige solid (64% yield).

¹ H NMR ( D₆ !DMSO, 400 MHz):δ=1.92 (s, 3H); 3.10 (m, 2H); 3.35 (m, 2H);6.60 (br. s, 2H); 6.72 (br. s, 1H); 7.00 (d, J=6.3 Hz, 1H).

¹³ C NMR ( D₆ !DMSO, 100 MHz):δ=25.39 (CH₃); 36.89 (CH₂); 41.51 (CH₂);105.37 (C); 131.96 (CH); 166.66 (C═O); 170.33 (C═O).

We claim:
 1. Process for preparing1,4,5,6-tetrahydropyrazine-2-carboxamides of the formula: ##STR5## whereR¹ is hydrogen, a C₁₋₃₀ -alkyl radical, a cycloaliphatic radical having3 to 8 ring members, a monocyclic aromatic radical which may optionallybe substituted by C₁₋₄ -alkyl groups or halogens, or an aryl-substitutedalkyl radical having 7 to 12 carbon atoms, where aryl is monocyclic,1-naphthyl or 2-naphthyl,(a) R² is a C₁₋₆ -alkyl radical, an arylradical where aryl is monocyclic, 1-naphthyl or 2-naphthyl, which mayoptionally be substituted by C₁₋₄ -alkyl groups or halogens, or anaryl-substituted alkyl radical, where aryl is monocyclic, 1 -naphthyl or2-naphthyl, and R³, R⁴ and R⁵ independently of one another are eachhydrogen, C₁₋₆ -alkyl radicals, aryl radicals, where aryl is monocyclic,1-naphthyl or 2-naphthyl, or aryl-substituted alkyl radicals, where arylis monocyclic, 1-naphthyl or 2-naphthyl, or (b) R² joins with R³ or R⁴and the adjacent carbon atom(s) to form a mono- or alicyclic systemwhich may optionally be substituted by one or more C₁₋₄ -alkyl groups,and R⁵ and R⁴ or R³ are each as defined above, and R⁶ is hydrogen or agroup of the formula R⁷ --C(═O)-- where R⁷ is hydrogen or optionallysubstituted C₁₋₆ -alkyl,characterized in that a2-cyano-1,4,5,6-tetrahydropyrazine of the formula: ##STR6## where R¹ isas defined above, or a salt thereof, is reacted in the presence of astrong acid with a compound of the formula: ##STR7## where R², R³, R⁴and R⁵ are each as defined above, and optionally with a carboxylic acidof the formula:

    R.sup.7 --COOH                                             IV

where R⁷ is as defined above, and the resulting nitrilium compound ishydrolyzed to the amide (I).
 2. Process according to claim 1,characterized in that the reaction of the2-cyano-1,4,5,6-tetrahydropyrazine (II) with the compound IIIa iscarried out in the presence of a carboxylic acid (IV) and a1-acyl-1,4,5,6-tetrahydropyrazine-2-carboxamide (I) where R⁶ is a groupof the formula R⁷ -C(═O)-- is obtained.
 3. Process according to claim 2,characterized in that the carboxylic acid used is acetic acid ortrifluoroacetic acid.
 4. Process according to claim 3, characterized inthat the 2-cyano-1,4,5,6-tetrahydropyrazine used is2-cyano-1,4,5,6-tetrahydropyrazine which is unsubstituted in position 3(R¹ ═H).
 5. Process according to claim 4, characterized in that the2-cyano-1,4,5,6-tetrahydropyrazine is employed in the form of themonomethanesulfonate.
 6. Process according to claim 5, characterized inthat the strong acid used is methanesulfonic acid.
 7. Process accordingto claim 6, characterized in that the compound of the formula Ilia usedis isobutene.
 8. Process according to claim 1, wherein the2-cyano-1,4,5,6-tetrahydropyrazine used is2-cyano-1,4,5,6-tetrahydropyrazine which is unsubstituted in position 3(R¹ ═H).
 9. Process according to claim 8, wherein the2-cyano-1,4,5,6-tetrahydropyrazine is employed in the form of themonomethanesulfonate.
 10. Process according to claim 1, wherein thestrong acid used is methanesulfonic acid.
 11. Process according to claim1, wherein the compound of the formula IIIa used is isobutene. 12.Process according to claim 1, characterized in that R¹ is phenyl,1-naphthyl, 2-naphthyl, o-tolyl, m-tolyl, p-tolyl, a xylyl or achlorophenyl.
 13. Process according to claim 1, characterized in that R²is phenyl, 1-naphthyl, 2-naphthyl, o-tolyl, m-tolyl, p-tolyl, a xylyl ora chlorophenyl .
 14. Process according to claim 1, characterized in thatR¹ is benzyl, 1-phenylethyl or 2-phenylethyl.
 15. Process according toclaim 1, characterized in that R² is benzyl, 1 -phenylethyl or2-phenylethyl.
 16. Process for preparing 1 -acetyl-1,4,5,6-tetrahydropyrazine-2-tert-butylcarboxamide, comprising reacting2-cyano-1,4,5,6-tetrahydropyrazine in the presence methanesulfonic acidwith isobutene and with acetic acid to produce a nitrilium compound, andhydrolyzing the nitrilium compound to the product.